Disease relevance of ACADM

• Characterization of wild-type and an active site mutant of human medium chain acyl-CoA dehydrogenase after expression in Escherichia coli [1].

High impact information on ACADM

• Lys-304, the prevalent mutation site found in patients with medium-chain acyl-CoA dehydrogenase deficiency, is located approximately 20 A away from the active site of the enzyme [2].
• Crystal structures of medium-chain acyl-CoA dehydrogenase from pig liver mitochondria with and without substrate [2].
• The three-dimensional structure of medium-chain acyl-CoA dehydrogenase from pig mitochondria in the native form and that of a complex of the enzyme and a substrate (product) have been solved and refined by x-ray crystallographic methods at 2.4-A resolution to R factors of 0.172 and 0.173, respectively [2].
• 5-cis-Octenoyl-CoA, a putative metabolite of linolenic acid, was efficiently dehydrogenated by medium-chain acyl-CoA dehydrogenase (EC 1.3.99.3) to 2-trans-5-cis-octadienoyl-CoA, which was isomerized to 3,5-octadienoyl-CoA either by mitochondrial delta 3,delta 2-enoyl-CoA isomerase (EC 5.3.3.8) or by peroxisomal trifunctional enzyme [3].
• Nucleotide sequence of medium-chain acyl-CoA dehydrogenase mRNA and its expression in enzyme-deficient human tissue [4].

Biological context of ACADM

• Polymorphisms in the promoter region of the porcine acyl-coA dehydrogenase, medium-chain (ACADM) gene have no effect on fat deposition traits in a pig Iberian x Landrace cross [5].
• We observed synthesis of the protein in Escherichia coli cells transformed with this plasmid with measurable MCADH enzyme activity in cell extracts [1].
• Influence of alpha-CH-->NH substitution in C8-CoA on the kinetics of association and dissociation of ligands with medium chain acyl-CoA dehydrogenase [6].
• Crystal structures of the wild type and the Glu376Gly/Thr255Glu mutant of human medium-chain acyl-CoA dehydrogenase: influence of the location of the catalytic base on substrate specificity [7].
• Despite the overall sequence homology, the catalytic residue (E376) of medium chain acyl-CoA dehydrogenase is not conserved in isovaleryl- and long chain acyl-CoA dehydrogenases [8].

Anatomical context of ACADM

• MCAD deficiency was demonstrated in fibroblasts from nine patients and LCAD deficiency in fibroblasts from two patients [9].

Associations of ACADM with chemical compounds

• The wild-type enzyme is a yellow protein due to the content of stoichiometric FAD and had a specific activity which is 50% of MCADH purified from pig kidney [1].
• The large increase in shielding experienced by the C1 and C3 HD carbons in the HD-CoA/MCAD complex is proposed to arise from the ring current field from the isoalloxazine portion of the flavin cofactor [10].
• These changes in chemical shift are unexpected given the results of previous Raman studies which revealed that the C3=C2-C1=O HD enone fragment is polarized upon binding to MCAD such that the electron density at the C3 and C1 carbons is reduced, not increased (Pellet et al. Biochemistry 2000, 39, 13982-13992) [10].
• We investigated the influence of Glu-376-->Asp (E376D) mutation on the UV/visible spectral, thermodynamic, and kinetic properties for the interaction of structurally different types of CoA-ligands (viz., octenoyl-CoA, acetoacetyl-CoA, and indoleacryloyl-CoA) to human liver medium-chain acyl-CoA dehydrogenase (MCAD) [11].
• A series of 8-alkylmercapto-FAD analogues containing increasingly bulky substituents bind tightly to apo-ETF and can be reduced to the dihydroflavin level by octanoyl-CoA in the presence of catalytic levels of the medium-chain acyl-CoA dehydrogenase [12].

Other interactions of ACADM

• The catalytic activities of ETFR and ETFB are comparable when they mediate the transfer of reducing equivalents between medium chain acyl-CoA dehydrogenase and 2,6-dichlorophenolindophenol [13].
• A range of 4-thiaacyl-CoA derivatives has been synthesized to study the bioactivation of cytotoxic fatty acids by the mitochondrial medium-chain acyl-CoA dehydrogenase and the peroxisomal acyl-CoA oxidase [14].
• The catalytic base responsible for the alpha-proton abstraction from the thioester substrate is Glu376 in MCADH, while that in LCADH is Glu255 (MCADH numbering), located over 100 residues away in its primary amino acid sequence [7].

Analytical, diagnostic and therapeutic context of ACADM

• Isothermal titration calorimetric studies for the binding of IACoA to MCAD reveal that the overall binding energy at 25 degrees C (delta G degree = -7.4 kcal/mol) is contributed almost equally by the enthalpic (delta H degree = -3.7 kcal/mol) and entropic (T delta S degree = 3.7 kcal/mol) changes [15].
• Probing hydrogen-bonding interactions in the active site of medium-chain acyl-CoA dehydrogenase using Raman spectroscopy [16].

References